Ex Parte Bourn et al

Patent Trial and Appeal Board

Dec 12, 2018

13061940 (P.T.A.B. Dec. 12, 2018)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
13/061,940 08/04/2011
24280 7590 12/14/2018
CHOATE, HALL & STEWARTLLP
TWO INTERNATIONAL PLACE
BOSTON, MA 02110
FIRST NAMED INVENTOR
William Bourn
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www .uspto.gov
ATTORNEY DOCKET NO. CONFIRMATION NO.
1424
EXAMINER
HUTSON, RICHARD G
ART UNIT PAPER NUMBER
1652
NOTIFICATION DATE DELIVERY MODE
12/14/2018 ELECTRONIC
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address(es):
patentdocket@choate.com
jnease@choate.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte WILLIAM BOURN, MARYKE APPEL, GA VIN RUSH, JOHN
FOSKETT, and PAUL McEW AN
Appeal2017-004400
Application 13/061,940 1
Technology Center 1600
Before JEFFREYN. FREDMAN, MICHAEL J. FITZPATRICK, and
RACHEL H. TOWNSEND, Administrative Patent Judges.
TOWNSEND, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to modified
Thermus aquaticus (Taq) DNA polymerase, which have been rejected as not
being adequately described in the Specification. We have jurisdiction under
35 U.S.C. § 6(b). Oral argument took place on December 6, 2018.
We reverse.
1 Appellants identify the real party in interest as Kapa Biosystems, Inc.,
which is a wholly owned subsidiary of Roche Molecular Systems, Inc.,
which is an indirect subsidiary of Roche Holding Ltd, which is the ultimate
holding company for the Roche Group of companies. (Appeal Br. 4.)
Appeal2017-004400
Application 13/061,940
STATEMENT OF THE CASE
"DNA polymerases are a family of enzymes that use single-stranded
DNA as a template to synthesize the complementary DNA strand." (Spec. ,r
2.) "Most DNA polymerases are multifunctional proteins that possess both
polymerizing and exonucleolytic activities." (Id.) The invention is directed
to a modified DNA polymerase that has polymerase activity and has
increased salt-tolerance with respect to that activity relative to a specific
wild-type Thermus aquaticus (Taq) DNA polymerase, and has 95% amino
acid sequence identity with that Taq DNA polymerase, as well as a
substitution relative to that Taq DNA polymerase at position 507. The
substitution is the amino acid lysine (K) for the wild type amino acid
glutamate (E).
Claims 72-77 and 79 2 are on appeal. Claim 77 is representative and
reads as follows:
77. A modified Taq DNA polymerase that:
(i) has an amino acid sequence that has at least 95% amino acid
sequence identity with wild-type Taq DNA polymerase set out
in SEQ ID NO.: 1, but includes a substitution relative to SEQ
ID NO: 1 at a position corresponding to position 507 of SEQ ID
NO.: 1, which substitution is E507K; and
(ii) has polymerase activity in catalyzing DNA template-
directed synthesis of a DNA polynucleotide, which activity has
increased salt-tolerance relative to the wild-type Taq DNA
polymerase of SEQ ID NO.: 1
(Appeal Br. 18.)
2 Claim 79 is not under rejection, and "is considered allowable." (Reply Br.
2.)
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Application 13/061,940
The following ground of rejection by the Examiner is before us on
review:
Claims 72-77 under 35 U.S.C. § 112, first paragraph, as containing
subject matter which was not described in the specification in such a way as
to reasonably convey to one skilled in the relevant art that the inventor(s), at
the time the application was filed, had possession of the claimed invention.
(Ans. 2)
DISCUSSION
The Examiner finds that Appellants have failed to sufficiently
describe the claimed invention because "[t]here is no disclosure of any
particular structure to function/activity relationship in the disclosed species"
and the "specification also fails to describe sufficient representative species
of these modified Taq DNA polymerases by any identifying structural
characteristics or properties, for which no predictability of structure and
function is apparent." (Ans. 2-3.) The Examiner recognizes that the
Specification exemplifies 18 species within the claimed genus where the
modified Taq polymerase has the E507K substitution, but notes that those
polymerases also have additional substitutions. (See, e.g., Ans. 7.) The
Examiner contends that this is an insufficient representative number of
species and fails to demonstrate the requisite structure to function
relationship in light of additional data in Appellants' Specification. (Id. at
6-8.)
In particular, the Examiner notes that the Specification describes 3
species of Taq DNA polymerase that had high salt tolerance with respect to
polymerase activity, and having amino acid substitutions compared to the
wild type sequence but did not have the claimed E507K substitution. (Id.)
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Application 13/061,940
The Examiner also explains that the Specification describes 2 species of Taq
DNA polymerase that had the claimed E507K substitution, among other
amino acid variations, but did not exhibit high salt tolerance with respect to
polymerase activity. (Id. at 7-8.) The Examiner contends that in light of
this evidence Appellants "have not established a structure to function
relationship between the E507K substitution and increased high salt
tolerance." (Id. at 8.)
According to the Examiner, Novozymes A/S v. DuPont Nutrition
Biosciences APS, 723 F.3d 1336 (Fed. Cir. 2013) requires Appellants to
have "confirmed their predictions through individual variants or subclasses
of variants expected to possess the claimed properties" in order to meet the
written description requirement. (Id.)
The Examiner does not find the Declarations of Dr. Lawrence Loeb
and Dr. Carl Wittwer submitted by Appellants on January 7, 2016, and
February 18, 2016, respectively, sufficient to establish that the claimed
invention is supported by an adequate written description. (Id. at 9-10.) In
particular, the Examiner contends those declarations are not sufficient to
demonstrate "how the specification teaches those of ordinary skill in the art
that introduction of the E507K substitution into Taq DNA polymerase
correlates with the functional activity as claimed" because those declarations
direct their analysis of the data presented by the Specification "to 'increase
DNA polymerase activity', not to the specification of the description of a
structure to function relationship for the modified Taq DNA polymerase
having E507K substitution and an increased salt-tolerance relative to the
wild type Taq DNA polymerase of SEQ ID NO: 1." (Id.)
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Application 13/061,940
Finally, the Examiner notes that while Appellants provided
experimental data with the Response filed September 2, 2015 demonstrating,
among other things, "the E507K substitution is sufficient to confer
improvement on measures of processivity including, e.g., ability to amplify
DNA fragments at high salt concentration," such is not sufficient to
overcome the rejection because the data was not part of the Specification at
the time of filing. (Id. at 12.)
We disagree with the Examiner's finding that the claimed invention is
not sufficiently described, and instead find Appellants have the better
position. (Appeal Br. 12-14; Reply Br. 6-14). "To satisfy the written
description requirement, the applicant must convey with reasonable clarity
to those skilled in the art that, as of the filing date sought, he or she was in
possession of the invention, and demonstrate that by disclosure in the
specification of the patent." Novozymes, 723 F.3d at 1344 (internal
quotations and citations omitted). "[T]he test requires an objective inquiry
into the four comers of the specification from the perspective of a person of
ordinary skill in the art." Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d
1336, 1351 (Fed.Cir.2010) (en bane). Assessing the adequacy of the
disclosure for a generic claim requires us to consider "the existing
knowledge in the particular field, the extent and content of the prior art, the
maturity of the science or technology, [and] the predictability of the aspect at
issue." AbbVie Deutschland GmbH v. Janssen Biotech, Inc., 759 F.3d 1285,
1299 (Fed. Cir. 2014) (internal quotations omitted).
Regarding the invention set forth in claim 77, we note that Dr. Loeb
provides relevant information regarding background knowledge in the art.
Dr. Loeb has been working with DNA polymerases for the last 40 years and
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Application 13/061,940
has published 250 or so peer-reviewed papers on DNA polymerases. (Loeb
Declaration ,r 2.) Dr. Loeb states that DNA polymerase is a highly
conserved enzyme and has high sequence conservation of amino acid
sequences between species. (Loeb Declaration ,r,r 7-9.) Consistent with the
foregoing, Ma, 3 a reference the Examiner relied upon during prosecution,
notes that it was known in the art that many polymerases not only share
sequence similarity, but also structural homology. (Ma 28:48-50 (citing
Doublie et al., 391 Nature 251 (1998)).)
Dr. Loeb also indicates that while "it has not been feasible to predict
the phenotypic changes induced by single amino acid substitutions" of DNA
polymerases (Loeb Declaration ,r 8), "it has been feasible to identify unique
substitutions in one species and predict with high probability that the same
substitution in another species will yield similar changes in properties"
(Loeb Declaration ,r 9).
In addition, Dr. Loeb states that "those skilled in the art understand
that common substitutions (i.e., substitutions that are present in multiple
self-amplified clones) are likely to yield similar properties even in the
presence of multiple other substitutions." (Loeb Declaration ,r 11.)
Dr. Loeb explained this reasonable expectation in the context of a prior art
experiment where substitutions of random sequences for motif A in the wild
type Taq DNA polymerase were studied and it was noted that "[t]wenty
three ... mutants encoded amino acid substitutions that allowed the
incorporation of ribonucleotides in place of the corresponding
deoxyribonucleotide" and that "substitution of aspartic acid for Glu615
3 Ma et al., US 6,759,226 Bl, issued July 6, 2004.
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Application 13/061,940
facilitates the incorporation of ribonucleotides in the context of multiple
mutations at other sites." (Id. ,r 10.)
Furthermore, the Specification indicates that the methods for
mutagenesis were well-known in the art, and also notes that assays for
testing for polymerase activity were well-known in the art. (Specification ,r,r
66-67.)
Claim 77 requires the following structural elements in the modified
Taq DNA polymerase: (a) that it have 95% amino acid sequence homology
with the wild-type Taq DNA polymerase provided in SEQ ID NO.: 1, and (b)
a lysine at position 507. In addition, claim 77 requires the foregoing
structure have the following function polymerase activity that has increased
salt-tolerance relative to the wild-type Taq of SEQ ID NO.: 1. As the
Examiner recognized, Appellants' Specification identifies 18 examples of
such modified Taq polymerases that were in fact made. (Spec. ,r,r 111-113;
see Appeal Br. 12.) This is not a case in which Appellants had merely
"fonnal textual support for each individual limitation," Ariad, 598 F .3d at
1349, and a "[a] 'mere wish or plan' for obtaining the claimed invention,"
id. at 1344 (quoting Regents of the Univ. of Cal. v. Eli Lilly & Co., 119 F.3d
1559, 1566 (Fed. Cir. 1997)). Instead, Appellants made several polymerases
within the scope of the invention.
Furthermore, these polymerases were made by directed evolution.
(Reply Br. 3; Loeb Declaration ,r 11.) In the process, Taq polymerase
amplified its own coding sequence under certain conditions which
introduced substitutions in the sequence. (Id.) Variants were cloned and
required to further self-amplify under selected pressure, one such condition
being high salt concentration. (Id.) "Ultimately, the directed evolution
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Application 13/061,940
system permit[ted] isolation of the DNA sequence encoding each successful
variant." (Id. at 4) The clones were characterized, including by assessing
polymerase activity. (Id.)
As Dr. Wittwer explained, "E507K is the single, most prevalent
modification in clones that were selected in the experiments described in the
... Application. As can be seen in Tables 3 and 4, a substitution at E507
was present in 20/23 clones." (Wittwer Declaration ,r 9.) Dr. Wittwer
further notes that "Table 12 demonstrates that a majority of assayed clones
that show resistance to high salt concentrations have a substitution at E507
(18/21)." (Id.) Indeed, the Examiner recognizes that the Specification
describes 18 clones that contained an E507K substitution among a number
of additional substitutions and had high salt tolerance. (Ans. 6.) It is true
that 3 of the 21 clones did not have a polymerase with an E507K
substitution. However, such does not establish E507K substitution would
not be expected to provide high salt tolerance to a Taq DNA polymerase
meeting the other requirements of claim 77. To the contrary, as Dr. Loeb
indicates, based on Appellants' disclosure, this common substitution that is
present in multiple self-amplified clones would have indicated to one of
ordinary skill in the art that an E507K substitution would reasonably be
expected to result in high salt tolerance "even in the presence of multiple
other substitutions." (Loeb Declaration ,r 11.)
This factual setting is unlike that in Novozymes, which the Examiner
relies on to conclude there is a lack of written description. Claim 1 at issue
in Novozymes is indeed very similar to claim 77. 4 However, in Novozymes
4 Claim 1 at issue in Novozymes was:
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Application 13/061,940
the "application ... contain[ ed] no disclosure of any variant that actually
satisfies the claims, nor [was] there anything to suggest that Novozymes
actually possessed such a variant at the time of filing," Novozymes, 723 F.
3d at 1348. Here, on the contrary, Appellants made 18 different clones that
meet the claimed functionality of high salt tolerance and polymerase
activity. Moreover, the testimony of Dr. Loeb establishes that at the time of
filing one of ordinary skill in the art would have understood from
Appellants' evidence of the common substitution at 507 of K for E that
resulted in high salt tolerance in the present of other substitutions in 18 self-
amplified clones, that similar properties would result with that substitution
even in the presence of multiple other substitutions in other clones. While it
is true, as the Examiner noted, that two clones that had an E507K
substitution, among a number of additional substitutions, did not show high
salt tolerance (Ans. 6), "[i]t is not necessary that every permutation within a
generally operable invention be effective in order for an inventor to obtain a
generic claim," Capon v Eshhar, 418 F.3d 1349, 1359 (Fed. Cir. 2005). We
conclude that in light of the state of the art, and the knowledge of one of skill
1. An isolated variant of a parent alpha-amylase, wherein:
(a) the variant has at least 90% sequence identity to SEQ ID NO: 6
[BSG alpha-amylase],
(b) the variant comprises a substitution of serine at position 239
relative to the parent alpha-amylase, using the amino acid sequence of
SEQ ID NO: 8 [BLA alpha-amylase] for determining position
numbering, and
( c) the variant has increased thermo stability relative to the parent
alpha-amylase, wherein thermostability is determined at pH 4.5, 90°
C. and 5 ppm calcium and has alpha-amylase activity.
Novozymes, 723 F.3d at 1341.
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Application 13/061,940
in the art, as well as the variety of examples made by Appellants, that there
is a preponderance of evidence establishing that Appellants' 18 clones are a
representative number of species of the claimed genus of modified Taq DNA
polymerases.
Furthermore, though not necessary to our conclusion that the
Examiner's written description rejection should be reversed, we conclude
that Appellants have provided a sufficient disclosure of "structural features
common to the members of the genus so that one of skill in the art can
visualize or recognize the members of the genus." AbbVie, 759 F.3d at 1299
(internal citations and quotations omitted). Dr. Wittwer explained that the
process that identified E507K substitution was directed evolution
experiments in which
libraries were initially subjected to stringent selection pressure
during the directed evolution experiment in the foml of high
concentrations of sait or intercalating dye in a PCR reaction.
Only clones that performed better than wild type Taq
"survived" these selections so that clones with advantageous
phenotypes would become the dominant/most prevalent clones .
. . . . Those skilled in the art are familiar with directed evolution
strategies and, reading the ... Application, would understand
that it was expected that only DNA polymerases that have
modifications that confer advantageous phenotypic
characteristics "survive" the selection part of the directed
evolution experiment.
The ... Application lists, in Table 2, each of the modifications
that was found in any "surviving" clone; Table 2 therefore
represents the set of modifications that the ... Application
teaches might confer the advantageous phenotypes, including
resistance to high-salt and intercalating dye as in the early stage
of the selection process.
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Application 13/061,940
The clones listed in Table 3 were picked from the directed
evolution experiment where high salt concentration was used as
the selection pressure.
The Kapa Application then goes on to study each of the
surviving clones ( each of which, as noted, contains multiple
modifications) in a variety of different assays that assess
aspects of their activities relevant to polymerase chain reaction
("PCR") amplification. In particular:
(i) resistance to certain high salt conditions (see, e.g.,
Example 5, and Table 12) ....
(Wittwer Declaration ,r,r 4--7.) Dr. Wittwer explains that "Table 12
demonstrates that a majority of assayed clones that show resistance to high
salt concentrations have a substitution at E507 ( 18/21 )." (Id. ,r 9.)
Dr. Wittwer concludes that
the . . . Application specifically demonstrates that modified
Taq DNA polymerases that have a modification at E507, and
particularly that contain E507K, can have increased polymerase
activity in catalyzing template-directed synthesis of a DNA
polynucleotide relative to wild type Taq. Thus, I can
confidently state that one of ordinary skill, reading the ...
Application, would understand it to describe E507-modified
Taq polymerases with increased DNA polymerization activity,
and specifically with increased polymerase activity in
catalyzing template-directed synthesis of a DNA polynucleotide
relative to wild type Taq under the conditions tested in the ...
Application. That is, the ... Application establishes that an
E507K substitution is very likely sufficient to confer increased
DNA polymerization activity (and specifically polymerase
activity in catalyzing template-directed synthesis of a DNA
polynudeotide)
(Wittwer Declaration ,r 10.) In other words, Dr. Wittwer provides testimony
indicating the clones of Table 12 that had E507K had polymerase activity
and that activity has increased salt-tolerance relative to the wild type Taq
DNA polymerase of SEQ ID NO.: 1. This testimony, is also supported by
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the evidence already discussed above that DNA polymerases such as Taq
share a number of well-known, common conserved regions. Thus, we
conclude that there is sufficient disclosure of structural features common to
the members of the genus so that one of skill in the art can visualize or
recognize the members of the genus.
SUMMARY
In light of the foregoing, we reverse the rejection of claims 72-77
under 35 U.S.C. § 112, first paragraph, as containing subject matter which
was not adequately described in the specification.
REVERSED
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